The taste periphery comprises a distributed array of taste buds innervated by distinct cranial nerves. In recent years, theories of the embryonic development of this system have undergone radical revision. Previously, taste buds were thought to be induced from indifferent epithelium by in growth of taste nerves; but new results demonstrate that early events in taste bud development occur before, and in the total absence of, innervation, raising anew questions of how taste buds develop. We now propose to examine this problem by taking advantage of the excellent molecular genetics of the mouse model system. In mice, lingual taste buds are restricted to papillae, which form by mid-gestation and likely contain taste bud progenitors; yet taste buds proper do not appear until postnatal stages. Two signaling factors (Sonic Hedgehog [Shh] and Bone Morphogenetic Proteins [BMPs]) are expressed in a subset of papillary epithelial cells, and both pathways influence murine taste development. Our preliminary data suggest that the Shh- expressing cells may be taste bud stem cells. And our newest findings implicate yet another, crucial signaling system, the Wnt pathway, in taste organ development, as gain or loss of Wnt signaling in embryonic tongues significantly affects papillae. Interactions of these 3 signaling pathways (Wnt, Shh and BMP) are known to drive development of many other epithelial specializations, including hair, feather and teeth, but their precise roles in taste organ development are unknown. With a nerve-independent view of early taste organ development, and a molecular genetic approach, we are now poised to work out the molecular mechanisms governing development of this vital sensory system. In the following 3 aims, we will test the overall hypothesis that: Taste buds originate from embryonic Shh-expressing stem cells whose development is regulated by interactions of the Wnt, Shh and BMP pathways. Aim 1: Ascertain whether embryonic Shh-expressing taste placode cells are taste bud stem cells. Aim 2: Determine how Wnts interact with BMP and Shh to regulate taste organ development. Aim 3: Test if epithelial Wnt signaling is sufficient for taste organ development. Successful completion of these aims is important for issues of human health related to taste function, as well as more generally to enhance knowledge of embryonic development and its misregulation. [unreadable] [unreadable] [unreadable]